A regulatory T cell Notch4-GDF15 axis licenses tissue inflammation in asthma

Harb H., Stephen-Victor E., Crestani E., Benamar M., Massoud A., Cui Y., ...Daha Fazla

NATURE IMMUNOLOGY, cilt.21, sa.11, ss.1359-1386, 2020 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 21 Sayı: 11
  • Basım Tarihi: 2020
  • Doi Numarası: 10.1038/s41590-020-0777-3
  • Dergi Adı: NATURE IMMUNOLOGY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Agricultural & Environmental Science Database, BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, EMBASE, MEDLINE, Veterinary Science Database
  • Sayfa Sayıları: ss.1359-1386
  • Marmara Üniversitesi Adresli: Evet

Özet

Elucidating the mechanisms that sustain asthmatic inflammation is critical for precision therapies. We found that interleukin-6- and STAT3 transcription factor-dependent upregulation of Notch4 receptor on lung tissue regulatory T (T-reg) cells is necessary for allergens and particulate matter pollutants to promote airway inflammation. Notch4 subverted T(reg)cells into the type 2 and type 17 helper (T(H)2 and T(H)17) effector T cells by Wnt and Hippo pathway-dependent mechanisms. Wnt activation induced growth and differentiation factor 15 expression in T(reg)cells, which activated group 2 innate lymphoid cells to provide a feed-forward mechanism for aggravated inflammation. Notch4, Wnt and Hippo were upregulated in circulating T(reg)cells of individuals with asthma as a function of disease severity, in association with reduced T(reg)cell-mediated suppression. Our studies thus identify Notch4-mediated immune tolerance subversion as a fundamental mechanism that licenses tissue inflammation in asthma.